JAK belongs to tyrosine kinase family participating in inflammation, autoimmune diseases, proliferative diseases, transplant rejection, diseases relating to cartilage turnover impairment, achondrogenesis and/or diseases related to hypersecretion of IL6.
The present invention also provides a compound, a method for preparing the compound and a composition comprising the same, and a method for preventing and/or treating inflammation, autoimmune diseases, proliferative diseases, transplant rejection, diseases relating to cartilage turnover impairment, achondrogenesis and/or diseases related to hypersecretion of IL6 by administrating the compound of the present invention.
Janus kinase (JAK) is a cytoplasm tyrosine kinase transducing cytokine signal from a membrane receptor to STAT transcription factor. There are four JAK family members including JAK1, JAK2, JAK3 and TYK2 in prior art. When a cytokine combine with its receptor, the JAK family members get autophosphorylated and/or transphosphorylated with each other, then STATs are phosphorylated and move into nucleus to regulate transcription. The JAK-STAT cellular signal pathway goes for interferon, most interleukins, multiple cytokines and endocrine factors, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL (Vain chenker W. etc. (2008)).
Combination research of genetic models and micro molecule JAK inhibitor discloses the therapeutic potency of several JAKs. It is confirmed through genetic studies of mouse and human that JAK3 is an immunosuppression target (O'SheaJ. etc. (2004)). JAK3 inhibitor has been successfully used in clinical development, and was used in organ transplantation rejection initially, and afterwards also was used in other immune inflammation indications, such as rheumatoid arthritis (RA), psoriasis and crohn disease (http://clinicaltrials.gov/). TYK2 is a potential target of immunoinflammatory disease, which has been confirmed through human genetic study and knockout research of mouse (Levy D. and Loomis C. (2007)). JAK1 is a new target of the field of immunoinflammatory disease. JAK1 is heterodimerized with other JAKs to transduce pro-inflammatory signal actuated by cytokines. Therefore, it is expected that JAK1 and/or other JAKs have therapeutic benefit to a series of inflammatory diseases and other diseases driven by signal transduction mediated by JAK.
Tofacitinib was developed by Pfizer, related patents are WO02/096909, U.S. Pat. No. 7,301,023 and WO2015087201, and it was successfully launched in America on Nov. 7, 2012 for the treatment of rheumatoid arthritis and Crohn's disease with the proprietaryname of Xeljanz®.
The patents for Filgotinib include U.S. Pat. No. 8,808,764 and WO2009047514A1, and Filgotinib is selective Jk1 inhibitor developed by Galapagos Company and used for the rheumatoid arthritis and Crohn's disease, and it is now in phase II clinical trials. It was reported that the active Jak1 IC50=10 nM Jak2 IC50=28 nM.
